The present invention relates generally to a novel process for the preparation of (R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[1,2-xcex1] imidazol-2-one. This compound is useful as an intermediate in the preparation of certain small molecules that are useful in the treatment or prevention of inflammatory and immune cell-mediated diseases. The present invention also relates to certain novel intermediates used in this novel process.
(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-5-iodo-3-methyl-1-H-imidazo[ 1,2-xcex1]-imidazol-2-one (1) is an advanced intermediate used in the preparation of certain small molecules that inhibit the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especially CD18/CD11a or xe2x80x9cLFA-1xe2x80x9d). As a result, these small molecules are useful in the treatment or prevention of inflammatory and immune cell-mediated diseases. See U.S. Nonprovisional Application No. 09/604,312 (Attorney Docket No. 9/162), Wu et al., filed on Jun. 27, 2000, herein incorporated by 
reference.
The method that has been used to prepare compound 1 is illustrated in Scheme 1 below. 
In this procedure, an amino-ester 2 was reacted with 3,5-dichlorophenylisothiocyanate 3 to provide thiohydantoin 4. To a solution of triphenylphosphine (PPh3) was added the azide 5. After stirring at room temperature overnight, thiohydantoin 4 was added to provide 6. Treatment of 6 with trifluoroacetic acid provided 7. Iodination was then carried out by reaction of 7 with N-iodosuccinimide and pyridinium p-toluenesulfonate to provide 1. Recovered 7 may be recycled to provide additional 1.
The present invention is directed to a novel process for the preparation of compound 1. A first aspect of the invention is directed to a process for preparing a compound of the formula 1: 
said process comprising the following steps:
a) reacting a compound of the formula I with a compound of the formula 
where R is C1-6alkyl, in an aprotic organic solvent, followed by adding a triarylphosphine, a carbon tetrahalide and a tertiary amine, to form a compound of the formula IIa where R is C1-6alkyl: 
b) optionally hydrolyzing a compound of the formula IIa produced in step a) by reacting the compound of formula Ha with a base to form a compound of the formula IIb: 
c) reacting a compound of the formula IIa produced in step a) with a Lewis acid and a phosphine oxide compound of the formula (R1)3PO, wherein R1 is C1-6alkyl or aryl, in an aprotic organic solvent to form a compound of the formula III: 
or
when the optional step b) is performed, reacting a compound of the formula IIb produced in step b) with a coupling agent in an aprotic organic solvent to form a compound of the formula III: 
d) reacting a compound of the formula III produced in step c) with a strong base and a compound of the formula (R2O)2POCl, wherein R2 is C1-6alkyl or aryl, in a polar organic solvent at a temperature of about xe2x88x9290xc2x0 C. to form a compound of the formula IV where R2 is C1-6alkyl or aryl: 
e) reacting a compound of the formula IV produced in step d) with trimethylsilyl iodide, or with sodium iodide and trimethylsilyl chloride, in an aprotic organic solvent to form a compound of the formula 1: 
A second aspect of the invention is directed to the individual novel steps of the above inventive process. A third aspect of the invention is directed to the novel intermediates IIa, IIb, III and IV. A final aspect of the invention is directed to the novel urea intermediate of the following formula Ia produced in the first step of the inventive process and its process of preparation: 
wherein R is C1-6alkyl.